Outline

Objective

The continuous loss of dopaminergic neurons mainly in the nigrostriatal system lead to the neurodegenerative disorder called Parkinson’s disease (PD). Since promising strategies for treating PD as neurotransplantation of foetal brain tissue pose considerable ethical constraints, therefore is a need for alternative cell resources. One of these sources may be the adult mammalian brain which possesses stem/progenitor cells with the potential of migration and differentiation. Throughout adult life persisting neural stem cells of the subventricular zone (SVZ) and RMS generate neuroblasts which migrate over a long distance and ultimately differentiate into tyrosinhydroxylase positive (TH+) and GABAergic interneurons in the olfactory bulb. The aim of this study was to determine whether the exploitation of neuroblasts of the forebrain might be useful to ameliorate PD symptoms and to restore the dopaminergic system.

Methods

In a short term study (STS) (5 rats) and a long-term study (LTS) (19 rats) all subjects received unilateral stereotactic injections with 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. Another 6 animals served as non-lesioned controls in the LTS. Drug-induced rotation tests were assessed to prove the lesion effect. Additionally, the LTS animals were tested in skilled forelimb behaviour. The RMS of P11 transgenic mice ubiquitously expressing GFP (kras-GFP) were explanted, dissociated, and subsequently transplanted into the striatum of these rats which obtained immunosuppression just before the transplantation and until the perfusion. All the animals were tested again in the rotation tests and the LTS animals performed the skilled forelimb behaviour test. Finally, all animals were perfused and the immunohistology against TH and GFP was analysed.

Results

Histological analysis show GFP positive cells (300-1000 cells per graft) which were widely distributed in the host striatum exhibiting elaborate dendritic arborizations covered by spines, both in the short term as well as in the long-term experiment. TH positive cells (100-600 cells per graft) were found only in the STS, but not in the LTS. In parallel, rotation tests revealed functional improvement only in the STS, but not in the LTS. No effects were seen in the skilled forelimb behaviour.

Conclusions

Therefore, RMS- derived cells seem to be a promising cell source for a cell-based restorative approach in the dopaminergic nigrostriatal system, and potentially also in Parkinson's disease.